Self-hardening calcium phosphate cements (CPC) have been used for bone and tooth restoration and for local drug delivery applications. See, for example, Larsson et al, “Use of injectable calcium phosphate cement for fracture fixation: A review,” Clinical Orthopedics and Related Research, 395:23-32 (2002) and Oda et al, “Clinical use of a newly developed calcium phosphate cement (XSB-671D),” Journal of Orthopedic Science, 11(2):167-174 (2006). The cements in powder form are typically mixed with an aqueous solution immediately before application. In the clinical situation, the ability of the surgeon to properly mix the cement powder and hydrating liquid and then place the cement paste in a defect within the prescribed time is a crucial factor in achieving optimum results. Specifically, the dry cement powder material needs to be mixed with an aqueous solution in the surgical setting, i.e., the operating room, transferred to an applicator, typically a syringe, and delivered to the desired location within the setting time. Conventional cements generally have a setting time of about 15-30 minutes. However, the methods used for mixing and transfer of cement for injection in the operating room are technically difficult and pose a risk for non-optimal material performance, e.g., early setting renders materials difficult to inject or causes phase separation, so-called filter pressing. Further, for technical reasons and time constraints, the material is typically mixed with a hydrating liquid in bulk to form a paste and the paste is then transferred to smaller syringes for delivery. In practice, material is often wasted due to an early setting reaction, i.e., the hydrated material sets to a hardened cement prior to delivery to the desired location, or because more material than is needed is mixed. A solution to these problems that includes the possibility to deliver material in smaller quantities in a more controlled manner is thus desired. Additionally, handling premixed formulations can be problematic if they are too viscous to deliver by injection.
The problem of obtaining a proper mix of the powder material and hydrating liquid for optimum clinical results in apatite cements has been addressed in US 2006/0263443, US 2007/0092856, Carey et al, “Premixed rapid-setting calcium phosphate composites for bone repair,” Biomaterials, 26(24):5002-5014 (2005), Takagi et al, “Premixed calcium-phosphate cement pastes,” Journal of Biomedical Materials Research Part B-Applied Biomaterials, 67B(2):689-696 (2003), Xu et al, “Premixed macroporous calcium phosphate cement scaffold,” Journal of Materials Science-Materials in Medicine, 18(7):1345-1353 (2007), and Xu et al, “Premixed calcium phosphate cements: Synthesis, physical properties, and cell cytotoxicity,” Dental Materials, 23(4):433-441 (2007), wherein premixed pastes are described. In US 2006/0263443, for example, a powder composition for hydroxyapatite is premixed with an organic acid and glycerol to form a paste, which paste may subsequently be injected into a defect. The injected material hardens through the diffusion of body liquids into the biomaterial. The organic acid is added to increase resistance to washout and the end product after setting is apatite, which is known to have a long resorption time in vivo as described above. Also, compositions of β-tricalcium phosphate (β-TCP) and hydrated acid calcium phosphate in glycerin or polyethylene glycol have previously been described in CN 1919357, Han et al, “β-TCP/MCPM-based premixed calcium phosphate cements,” Acta Biomaterialia, doi:10.1016/j.actbio.2009.04.024 (2009) and Aberg et al, “Premixed acidic calcium phosphate cement: characterization of strength and microstructure, Journal of Biomedical Materials Research, 2010, May; 93(2):436-41. However, it is difficult to obtain sufficient shelf life using the described formulations in the prior art, as also noted by Shimada et al, Journal of Research of the National Institute of Standards and Technology “Properties of Injectable Apatite-Forming Premixed Cements,” 115(4): 240 (July-August 2010). Shelf life is also a problem for reactive Brushite forming cements. Tests have been performed using monocalcium phosphate anhydrous (MCPA), where difficulties to achieve a rapid setting time resulted when changing from MCPM (monocalcium phosphate monohydrate) to MCPA.
Thus, there is a continuing need to be able to efficiently prepare, store and safely deliver hydraulic cements, particularly for biomedical applications, i.e., hydraulic cements that overcome the above noted and/or other difficulties of conventional hydraulic cement materials, while optionally optimizing performance properties, particularly in vivo performance properties.